tbuckley/cabot-search huggingface dataset:
Abstract 5518: Use of antihypertensive drugs and the risk of cancer, findings of a population-based cohort study in Shanghai
Authors: Suna Wang, Li Xie, Ying Qian, Jie Wang, Guanglu Zhang, Lei Li, Weituo Zhang, Herbert Yu, Wensui Zhao, Biyun Qian
Journal: Cancer Research (2023)

Abstract Background: The widespread use of antihypertensive drugs has raised concerns on whether the use increases the risk of cancer. Although multiple studies have addressed this issue, it remains unclear if hypertension patients who are on antihypertensive medications are at higher risk for cancer. Methods: Between 2013 and 2017, we enrolled 101,370 individuals with hypertension from community healthcare centers in Changning Shanghai, followed through December 31, 2019. Drug administration was defined as the class and number of ever use the major antihypertensives. The main outcomes included the incidences of all cancer and major types of cancer in Shanghai (lung, colorectum, thyroid, and stomach). Results: During a mean follow-up of 5.1 (SD 1.3) years, 4970 cancer cases were newly diagnosed in the cohort. CCBs were the most frequently used antihypertensives which were associated with a moderately increased risk of all cancer (hazard ratio, HR: 1.11, 95% CI: 1.05-1.18). The second commonly used drug ARBs were also associated with increased risk of all cancer (HR: 1.10, 95%CI: 1.03-1.17) as well as lung and thyroid cancers (HR: 1.21, 95%CI: 1.05-1.39; HR: 1.66, 95%CI: 1.22-2.27, respectively). No cancer association was found with other antihypertensives. Individuals who use more than one class of antihypertensives had a higher risk of all cancer, and a possible dose-response relationship was suggested. Conclusions: Use of ARBs or CCBs may be associated with an increased risk of cancer. Taking more than one class of antihypertensives appeared to have a higher risk for cancer. Citation Format: Suna Wang, Li Xie, Ying Qian, Jie Wang, Guanglu Zhang, Lei Li, Weituo Zhang, Herbert Yu, Wensui Zhao, Biyun Qian. Use of antihypertensive drugs and the risk of cancer, findings of a population-based cohort study in Shanghai. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5518.
Abstract 557: EGFR-targeted mesenchymal stem cells for enhanced tumor retention and inhibition
Authors: Susheelkumar Nethi, Shubhmita Bhatnagar, Xiaolei Li, Swayam Prabha
Journal: Cancer Research (2023)

Abstract MSCs have been studied as gene therapy vehicles, and several preclinical and clinical studies support the use of genetically modified MSCs to deliver therapeutics to tumor tissues. We were one of the early groups to demonstrate that MSCs can be engineered to carry cytotoxic drugs by using nanoparticle-encapsulated form of the drug. However, tumor homing of MSCs is inefficient. We hypothesized that the targeting effectiveness of MSCs can be significantly improved by incorporating tumor-targeting ligands on the MSC surface that will allow for enhanced arrest and binding within the tumor tissue. In this study, we designed anti-EGFR Ab (cetuximab, Cmab) functionalized MSCs and studied the comparative therapeutic efficacy of paclitaxel-loaded, Cmab functionalized MSCs relative to that of paclitaxel-loaded, unfunctionalized MSCs. Cmab functionalized MSCs demonstrated improved binding to A549 adenocarcinoma cells. Mice bearing orthotopic A549 tumors were dosed i.v. with the various treatments. Similar to what we have shown previously, MSCs loaded with paclitaxel nanoparticles were effective in slowing tumor growth and improving the overall survival relative to that of other controls. However, the greatest inhibition of tumor growth was observed in mice that received anti-EGFR Ab functionalized, paclitaxel-loaded MSCs. Compared to a median survival of 21 days for saline and 27 days for paclitaxel-loaded MSC treated group and paclitaxel-loaded IgG functionalized MSCs, Cmab Ab functionalized, paclitaxel-loaded MSCs treated mice resulted in significantly improved median survival of 35 days (p&amp;lt;0.001). Biodistribution studies revealed a sixfold higher retention of functionalized MSCs when compared to unfunctionalized MSCs. These results demonstrate the potential for improved tumor targeting with EGFR-targeted MSCs. Citation Format: Susheelkumar Nethi, Shubhmita Bhatnagar, Xiaolei Li, Swayam Prabha. EGFR-targeted mesenchymal stem cells for enhanced tumor retention and inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 557.
Zoledronic acid and thymosin α1 elicit antitumor immunity against prostate cancer by enhancing tumor inflammation and cytotoxic T cells
Authors: Sheng Wang, Maohua Huang, Minfeng Chen, Zhiting Sun, Yubo Jiao, Geni Ye, Jinghua Pan, Wencai Ye, Jianfu Zhao, Dongmei Zhang
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Advanced or metastatic prostate cancer (PCa) is still an incurable malignancy with high lethality and a poor prognosis. Despite the remarkable success of immunotherapy against many types of cancer, most patients with PCa receive minimal benefit from current immunotherapeutic strategies, because PCa is an immune cold tumor with scarce T-cell infiltration in the tumor microenvironment. The aim of this study was to develop an effective immunotherapeutic approach for immune cold PCa tumors. Methods The therapeutic efficacy of androgen deprivation therapy (ADT) and zoledronic acid (ZA) plus thymosin α1 (Tα1) therapy was analyzed retrospectively in patients with advanced or metastatic PCa. The effects and mechanisms by which ZA and Tα1 regulated the immune functions of PCa cells and immune cells were evaluated by a PCa allograft mouse model, flow cytometric analysis, immunohistochemical and immunofluorescence staining assays, and PCR, ELISA, and Western blot analyses. Results In this study, clinical retrospective analysis revealed that ADT combined with ZA plus Tα1 improved the therapeutic outcomes of patients with PCa, which might be associated with an enhanced frequency of T cells. ZA and Tα1 treatment synergistically inhibited the growth of androgen-independent PCa allograft tumors, with increased infiltration of tumor-specific cytotoxic CD8 + T cells and enhanced tumor inflammation. Functionally, ZA and Tα1 treatment relieved immunosuppression in PCa cells, stimulated pro-inflammatory macrophages, and enhanced the cytotoxic function of T cells. Mechanistically, ZA plus Tα1 therapy blocked the MyD88/NF-κB pathway in PCa cells but activated this signaling in macrophages and T cells, altering the tumor immune landscape to suppress PCa progression. Conclusions These findings uncover a previously undefined role for ZA and Tα1 in inhibiting the disease progression of immune cold PCa tumors by enhancing antitumor immunity and pave the way for the application of ZA plus Tα1 therapy as an immunotherapeutic strategy for treating patients with immunologically unresponsive PCa.
Abstract 5081: Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models
Authors: Payton C. Laurie, Mary Ellen Molloy, Patrick P. Ng, Banmeet S. Anand
Journal: Cancer Research (2023)

Abstract HPN217 is a Tri-specific T Cell-Activating Construct (TriTAC) currently being evaluated in a phase 1 clinical trial for relapsed or refractory multiple myeloma (MM) (NCT04184050). It consists of a single domain antibody (sdAb) specific for B-cell maturation antigen (BCMA), a serum albumin-specific sdAb for half-life extension, and a single chain Fv (scFv) specific for the CD3ε subunit of the T cell receptor (TCR) complex for T cell engagement. BCMA is a cell surface receptor highly expressed on malignant plasma cells in MM patients and plays an important role in B-cell proliferation and survival. Soluble BCMA (sBCMA) is produced when the extracellular domain of BCMA is cleaved by γ-secretase and enters circulation. sBCMA may act as a sink for BCMA targeted therapies, potentially decreasing anti-tumor efficacy. Previous studies have shown γ-secretase inhibitors (GSIs) can increase membrane bound BCMA expression on MM cells and decrease sBCMA concentrations, providing a rationale for combining GSIs with HPN217. Here we describe preclinical studies evaluating that combination in vitro and in vivo. To evaluate the effects of GSIs on BCMA expression, MM cell lines MOLP8, KMS-12-BM, and MM.1S were incubated with GSIs LY3039478, PF03084014, or RO4929097overnight. GSI treatment led to a 3-7-fold increase in BCMA expression on MM cell surface. To determine the effects of increased BCMA expression mediated by GSIs on the activity of HPN217, an in vitro T cell dependent cell cytotoxicity assay (TDCC) was conducted. GSIs enhanced the activity of HPN217, in some cases leading to a 3.5-fold increase in potency compared to HPN217 alone. Next, the impact of the combination was tested in vivo using a disseminated MOLP-8 xenograft model engrafted with T cells from a healthy human donor. Vehicle treated mice succumbed to disease burden with a median survival of 23 days as assessed by body weight loss and clinical observations. A suboptimal dose of 4 ug/kg HPN217 protected mice from disease burden for an additional 3 days. By contrast, the combination of HPN217 and LY3039478 led to a significant increase in survival compared to vehicle or either monotherapy, with a median survival of 43 days. Taken together these results demonstrate the potential utility of GSIs to enhance the anti-tumor activity of HPN217 and supports further investigation of this combinatorial approach in patients. Citation Format: Payton C. Laurie, Mary Ellen Molloy, Patrick P. Ng, Banmeet S. Anand. Anti-tumor activity of HPN217, a BCMA-targeting tri-specific T cell engager, is enhanced by γ-secretase inhibitors in preclinical models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5081.
Matchtigs: minimum plain text representation of k-mer sets
Authors: Sebastian Schmidt, Shahbaz Khan, Jarno N. Alanko, Giulio E. Pibiri, Alexandru I. Tomescu
Journal: Genome biology (2023)

We propose a polynomial algorithm computing a minimum plain-text representation of k-mer sets, as well as an efficient near-minimum greedy heuristic. When compressing read sets of large model organisms or bacterial pangenomes, with only a minor runtime increase, we shrink the representation by up to 59% over unitigs and 26% over previous work. Additionally, the number of strings is decreased by up to 97% over unitigs and 90% over previous work. Finally, a small representation has advantages in downstream applications, as it speeds up SSHash-Lite queries by up to 4.26× over unitigs and 2.10× over previous work.
Safety and efficacy of an anti–human APC antibody for prophylaxis of congenital factor deficiencies in preclinical models
Authors: Miao Jiang, Fei Yang, Yizhi Jiang, Lu Cheng, Jingjing Han, Jiawei Yi, Bin Zuo, Lulu Huang, Zhenni Ma, Tianyi Li, Lijuan J. Cao, Zhisong Xia, Xia Bai, Chenjun Jia, Teddy Tat Chi Yang, Naomi L. Esmon, Changgeng Ruan, Lijun Xia, Charles T. Esmon, Yue Han, Depei Wu, Jun Xu
Journal: Blood (2023)
Targeting miR-126 in Ph+ acute lymphoblastic leukemia
Authors: Junjing Qiao, Dandan Zhao, Le Xuan Truong Nguyen, Fang Chen, Chen Liang, Katrina Estrella, Lucy Y. Ghoda, Nora Heisterkamp, Emanuela C. Marcucci, Ya-Huei Kuo, Guido Marcucci, Bin Zhang
Journal: Leukemia (2023)
Abstract 1149: Universal redirection of chimeric antigen receptor T cells against solid tumors via tumor cell membrane-inserting CAR ligands
Authors: Angela Zhang
Journal: Cancer Research (2023)

Abstract Chimeric antigen receptor (CAR) T cell therapy is effective in treating certain hematological malignancies, but its translation to solid tumors has been challenging. Selecting an effective target antigen is hampered by heterogeneous tumor antigen expression and target antigen expression in healthy tissues. We describe a strategy to promote CAR T-mediated destruction of any tumor via intratumoral administration of a membrane-inserting fluorescein isothiocyanate lipid amphiphile molecule (“amph-FITC”) recognizable by a FITC-specific CAR. Firstly, we show labeling of tumor cells with amph-FITC in vitro, mediating cytotoxicity by FITC CAR T cells in coculture. Then, we demonstrate efficient tagging of tumor cells in vivo upon intratumoral injection with minimal labeling of non-tumor tissues, driving FITC CAR T cell proliferation and accumulation in tumors. Subsequently, we determine that this strategy stimulates an anti-tumor response that facilitates tumor regression in several syngeneic and human xenograft mouse models bearing different tissues of origin. In syngeneic models, this strategy induced the infiltration of host T cells and elicited endogenous tumor-specific T cell priming, leading to protection against tumor rechallenge. These results demonstrate the capacity to treat tumors independent of antigen expression or tissue of origin, addressing a major bottleneck in adoptive T cell therapy. Citation Format: Angela Zhang. Universal redirection of chimeric antigen receptor T cells against solid tumors via tumor cell membrane-inserting CAR ligands [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1149.
Abstract 6637: Transcriptomic biomarkers of immunotherapy response in solid tumors
Authors: Balazs Gyorffy, Szonja Anna Kovacs, János Tibor Fekete
Journal: Cancer Research (2023)

Abstract Background. Immune-checkpoint inhibitors can be administered in multiple solid tumor types. Currently available biomarkers, like the expression of PD-L1 or tumor mutational burden, miss a significant proportion of patients who could benefit from the therapy. Our goal was to set up a database consisting of both gene expression and clinical response data and to uncover the most significant biomarkers of response to anti-PD-1, anti-PD-L1, and anti-CTLA-4 immunotherapies. Methods. The GEO repository was screened to identify datasets with simultaneously available transcriptomic and clinical response data across different solid tumor types. The screening focused on studies involving the administration of nivolumab (anti-PD-1), pembrolizumab (anti-PD-1), atezolizumab (anti-PD-L1), durvalumab (anti-PD-L1), and ipilimumab (anti-CTLA-4). Mann-Whitney U-test and receiver operating characteristic analysis were performed across all genes to identify features related to therapy response. False discovery rate was computed to correct for multiple hypothesis testing. Results. The database that we established consists of 1,439 unique tumor samples from nineteen datasets with gastric-, lung-, esophageal-, head, neck-, and urothelial cancers, and malignant melanoma. The strongest upregulated candidates linked to resistance in anti-PD-1 treated tumors were PRXL2A (AUC=0.771), ODR4 (AUC=0.734), and RBM15B (AUC=0.734). The most robust hits in the anti-PD-L1 treated cohort were NOTCH3 (AUC=0.639), NECTIN1 (AUC=0.631) and ITGAV (AUC=0.63). In the anti-CTLA-4 treatment cohort C5orf24 (AUC=0.76) was the most promising candidate. We have also established a portal for additional analysis and ranking of further biomarker candidates by extending our previously established ROC plotter. The immunotherapy-treated transcriptomic database is accessible at the website www.rocplot.com/immune. Discussion. An integrated database and an online platform were set up to validate potential biomarkers of immunotherapy response in a sizeable cohort of cancer samples from multiple tumor types. By using the direction of expression change as a filter, we have identified the most promising biomarker candidates. Citation Format: Balazs Gyorffy, Szonja Anna Kovacs, János Tibor Fekete. Transcriptomic biomarkers of immunotherapy response in solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6637.
Physics-informed neural networks for modeling physiological time series for cuffless blood pressure estimation
Authors: Kaan Sel, Amirmohammad Mohammadi, Roderic I. Pettigrew, Roozbeh Jafari
Journal: npj Digital Medicine (2023)

The bold vision of AI-driven pervasive physiological monitoring, through the proliferation of off-the-shelf wearables that began a decade ago, has created immense opportunities to extract actionable information for precision medicine. These AI algorithms model input-output relationships of a system that, in many cases, exhibits complex nature and personalization requirements. A particular example is cuffless blood pressure estimation using wearable bioimpedance. However, these algorithms need training over significant amount of ground truth data. In the context of biomedical applications, collecting ground truth data, particularly at the personalized level is challenging, burdensome, and in some cases infeasible. Our objective is to establish physics-informed neural network (PINN) models for physiological time series data that would use minimal ground truth information to extract complex cardiovascular information. We achieve this by building Taylor's approximation for gradually changing known cardiovascular relationships between input and output (e.g., sensor measurements to blood pressure) and incorporating this approximation into our proposed neural network training. The effectiveness of the framework is demonstrated through a case study: continuous cuffless BP estimation from time series bioimpedance data. We show that by using PINNs over the state-of-the-art time series models tested on the same datasets, we retain high correlations (systolic: 0.90, diastolic: 0.89) and low error (systolic: 1.3 ± 7.6 mmHg, diastolic: 0.6 ± 6.4 mmHg) while reducing the amount of ground truth training data on average by a factor of 15. This could be helpful in developing future AI algorithms to help interpret pervasive physiologic data using minimal amount of training data.
Lipid nanoparticles allow efficient and harmless ex vivo gene editing of human hematopoietic cells
Authors: Valentina Vavassori, Samuele Ferrari, Stefano Beretta, Claudia Asperti, Luisa Albano, Andrea Annoni, Chiara Gaddoni, Angelica Varesi, Monica Soldi, Alessandro Cuomo, Tiziana Bonaldi, Marina Radrizzani, Ivan Merelli, Luigi Naldini
Journal: Blood (2023)

Ex vivo gene editing in T cells and hematopoietic stem/progenitor cells (HSPCs) holds promise for treating diseases. Gene editing encompasses the delivery of a programmable editor RNA or ribonucleoprotein, often achieved ex vivo via electroporation, and when aiming for homology-driven correction of a DNA template, often provided by viral vectors together with a nuclease editor. Although HSPCs activate a robust p53-dependent DNA damage response upon nuclease-based editing, the responses triggered in T cells remain poorly characterized. Here, we performed comprehensive multiomics analyses and found that electroporation is the main culprit of cytotoxicity in T cells, causing death and cell cycle delay, perturbing metabolism, and inducing an inflammatory response. Nuclease RNA delivery using lipid nanoparticles (LNPs) nearly abolished cell death and ameliorated cell growth, improving tolerance to the procedure and yielding a higher number of edited cells compared with using electroporation. Transient transcriptomic changes upon LNP treatment were mostly caused by cellular loading with exogenous cholesterol, whose potentially detrimental impact could be overcome by limiting exposure. Notably, LNP-based HSPC editing dampened p53 pathway induction and supported higher clonogenic activity and similar or higher reconstitution by long-term repopulating HSPCs compared with electroporation, reaching comparable editing efficiencies. Overall, LNPs may allow efficient and harmless ex vivo gene editing in hematopoietic cells for the treatment of human diseases.
Abstract 1692: mTOR inhibition attenuates chemosensitivity through induction of a persister state
Authors: Yuanhui Liu, Nancy Azizian, Delaney Sullivan, Yulin Li
Journal: Cancer Research (2023)

Abstract Effective cancer therapeutics often kill a large fraction of tumor cells, while sparing a small surviving population, which can resurface as future tumor recurrence. Mechanisms of resistance in these residual tumors may involve rare preexisting clones with mutations, as well as de novo development of resistance through various genetic and/or non-genetic processes. In the context of acute stress resulting from cancer therapeutics, the initial adaptation is essential for tumor cell survival and allows for subsequent development of resistance through additional genetic and non-genetic mechanisms. As an integrator of environmental signals and cellular response, the mTOR pathway is a critical driver of cellular adaptation to environmental changes. In particular, mTOR regulates embryonic diapause, a reversible dormancy state in mammalian development in response to unfavorable environments. Analogous to its role in regulating embryonic diapause, mTOR inhibition may induce a diapause-like state in cancer cells, leading to drug tolerance and persistence of residual tumors following therapy. In line with this notion, recent studies have reported markedly reduced mTOR activity in residual tumors. However, the causal relationship between mTOR inhibition and chemosensitivity has not been investigated. Through a genome-wide CRISPR knockout library screen in pancreatic cancer cells treated with chemotherapeutic agents, we have identified the mTOR pathway as a prominent determinant of chemosensitivity. Pharmacological suppression of mTOR activity in cancer cells from diverse tissue origins leads to the persistence of a reversibly resistant population, which is otherwise eliminated by chemotherapeutic agents. Conversely, activation of the mTOR pathway increases chemosensitivity and predicts better survival among various human cancers. Survival of the persisters is dependent on the regulation of autophagy, G2/M checkpoint, and cell death pathways, as revealed by a small-molecule chemical library screen. Thus, mTOR plays a causal yet paradoxical role in regulating chemotherapeutic response; inhibition of the mTOR pathway, while suppressing tumor expansion, facilitates the development of a reversible drug-tolerant persister state. Citation Format: Yuanhui Liu, Nancy Azizian, Delaney Sullivan, Yulin Li. mTOR inhibition attenuates chemosensitivity through induction of a persister state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1692.